Malaria, a disease caused by parasitic protozoans in the genus Plasmodium, is transmitted by mosquitoes to humans. Each year, hundreds of millions of people are infected with this organism and 2-3 million fatalities result, mostly in young children. The problem is most severe in Africa, and is now worsening because of the increasing resistance of parasites to the inexpensive drugs used for prevention and control in the past. A second important strategy for control, reducing mosquito populations through insecticide use, is also threatened because of insecticide resistance, increasing costs and loss of trained personnel. A new target for research has been the interaction between the mosquito and the parasite. The long-term goal of the research presented here is to understand the molecular basis for incompatibility between mosquitoes and malaria parasites because this may suggest ways to enhance mechanisms that cause incompatibility through genetic or chemical manipulation of vector mosquitoes. The proposed research will focus on characterizing proteins and genes that are involved in the mosquito's humoral immune responses, which can lead to the death of parasites. Two proteins that are involved in melanization and killing of ookinetes in Anopheles gambiaewill be cloned and characterized and will be tested for parasite melanization using viral transduction systems. Other proteins and genes that are involved in the responses to parasites will be identified by electrophoretic analysis of in vivo radiolabeled polypeptides and differential display of mRNA molecules produced during parasite infections and humoral immune responses. These molecules will be characterized and tested for parasite-killing ability in vitro and in vivo.